Small Molecule Pak 1 Inhibitors May be an Effective Therapy for Colorectal Cancer
PHILADELPHIA– A new study suggests that targeting Group I p21-activated kinases (Paks) with small-molecule inhibitors could be a promising therapeutic approach in colorectal cancer. Researchers led by Jonathan Chernoff, MD, PhD, chief scientific officer at Fox Chase Cancer Center, designed a transgenic mouse model that conditionally expresses an inhibitory peptide to block the catalytic function of Group I Paks, and noted its efficacy in reducing adenomas and impeding progression to carcinomas. The paper appears in the journal Nature Communications.
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Group I Paks are associated with invasive and metastatic colorectal lesions, and previous studies have shown that they may be plausible drug targets. In this study the researchers designed a mouse that naturally expressed a small-molecule inhibitor to bind to the kinases and inhibit their enzyme activity. Importantly, Chernoff and his colleagues opted to breed the inhibitor into the mice rather than edit the gene to eliminate the Pak protein altogether. This approach provided a more realistic approximation of the way a drug could work in a cancer patient.
“We designed a model that closely mimics the effects of a small-molecule inhibitor that targets a known regulator of colorectal cancer formation and progression,” said Chernoff.
The mice that were bred with the small-molecule inhibitor developed dramatically fewer benign adenomas in the small and large intestine, and no malignant tumors. The group has already begun similar experiments to test the inhibition of Group II Paks as potential therapeutic targets for pancreatic cancer.